Abstract: Arthropod-borne and Rodent-borne viruses in the family Bunyaviridaes represent a serious threat to both human and animal health. Most recently emerged viruses are from this family and many Bunyaviridae have significant potential as bioterrorism (BT) agents. For example, Rift Valley Fever virus is considered by many to be an optimal BT agent because of its ability to emerge in new areas, to be lethal not only for humans but also for animal populations, and to be readily transmitted via aerosol. Despite these facts, there are virtually no safe or effective vaccines for bunyaviruses - especially vaccines for humans. In this project we will use the well-characterized LaCrosse virus (LACV) system to analyze the pathogenesis of infection of LACV transmitted either by aerosol or horizontally by the mosquito vector. We will develop LACV vector and aerosol transmission mouse models for the Bunyaviridae. In addition, we will determine the mechanism underlying the profound disease-enhancing effects of mosquito saliva for LACV infectivity and the salivary proteins responsible for this phenomenon. Armed with this information, we will then design vaccines (eg, Sindbis replicon, LANACs) that will protect against aerosol or mosquito-delivered LACV and other arboviruses in the Bunyaviridae as well as aerosol infection with selected Hantaviruses. Project Interactions: This project will interact extensively with other components of the RCE and with collaborators outside the RCE (Dr. Valenzuela, NIH). The Pis of the project are Drs. Richard Titus and Barry Beaty. Drs. Titus and Beaty are located in the Pathology building and Arthropod and Infectious Disease Laboratory, respectively. Dr. Titus provides the animal model/arthropod salivary potentiation while Dr. Beaty provides the virology/mosquito life cycle expertises to the project; thus, the project is only possible because of the interactions that will occur between the two groups. In addition, the project will interact with other investigators in the RCE. Specifically, with Drs. Kedl, Blair, Dow on LANACs studies (II.C.6.) Drs. Olson and Powers (II.B.) on arbovirus pathogenesis and replicon studies, Dr. Barnard (II.G.4.) on bunyavirus models, and Drs. Dandy and Grainger (H.B.6.), and other projects in Spore 2 and PORE 1. In addition, this project will be dependent upon 2 SFCs: Animal Models Core (III.A.) and Genomics/Proteomics Core (III.C.).